It is well known that the growth of normal lymphocytes is dependent not only on contact with an antigenic substance or a mitogen, but also on the presence of certain growth factors known as lymphokines. One of these growth factors is known as T-cell growth factor (TCGF) better known as interleukin-2 (IL-2). The discovery of this growth factor (Gillis, et al., Nature, 268; 154 (1977) and Ruscetti, et al., J. Immunol, 119; 131 (1977)) resulted in the large scale growth and cloning of T-lymphocytes as sources for IL-2.
The lymphocytes or white blood cells in the animal body come in two types, B-cells and T-cells. The B-cells produce antibodies in the form of immunoglobulins that bind onto invading organisms while the T-cells produce the lymphokines which are responsible for turning B-cells on or off. See for example Cell. Immunol. 36: 15 (1978); J. Cell Physiol. 96: 53 (1978); Eur. J. Immunol. 8: 681 (1978); Immunol. Rev. 54: 188 (1981); Immunol. Rev. 54: 158 (1981); J. Exp. Med. 154: 1500 (1981); National Cancer Institute Mon. 60: 211 (1982); Int. J. Cancer 28: 157 (1981); The Potential Role of T-Cell Subpopulations in Cancer Therapy, Eds. A. Fefer & A. Goldstein, Raven Press, N.Y. pp 173 et seq. (1982); J. Immunol, 128: (258) 1982.
The known types of lymphokines include, in addition to IL-2, B-cell factors, macrophage activation factor (MAF), Interleukin-3 (IL-3), Colony Stimulating Factor (CSF), Tumor Necrosis Factor, and other factors produced by monocytes such as Interleukin-1 (IL-1) and Gamma Interferon. All of these factors are secreted by white blood cells and are collectively known as cytokines. Great attention has been given to using various recombinant DNA techniques and other methodologies for cloning normal T and B cell lines that can produce these materials. See for example Nature 259: 130 (1976); Immunology 32: 319 (1977); Exp. Hemat, 8: 494 (1980); Nature 283: 581 (1980); Proc. Natl. Acad. Sci. U.S.A. 78: 1858 (1981); J. Immunol. Methods 49: 1 (1982); Nature 29424/31: 697-699 (1981), all of which are incorporated by reference.
The present invention is based on the discovery of a class of synthetic organic derivatives of tellurium or selenium that are capable of stimulating cytokine producing cells to produce significant quantities of cytokines both in vivo and in vitro. This discovery makes possible a novel therapeutic approach in the treatment of cancer, immune deficiencies, autoimmune diseases and infectious diseases.
Accordingly, it is an object of the invention to provide novel compounds based on tellurium or selenium that are useful as therapeutic agents.
It is also an object of the invention to provide a novel method for producing in vitro cytokines such as lymphokines and induce receptors to these cytokines.
It is also an object of the invention to produce in vivo cytokines such as lymphokines and and induce receptors to cytokines for the treatment of diseases such as cancer, immune deficiencies, autoimmune diseases and infectious diseases.
It is also an object of the invention to provide novel pharmaceutical compositions that are based on tellurium compounds that produce cytokines in vivo and in vitro.